Polybrominated diphenyl ethers (PBDEs) have been used as flame retardants in consumer products and are now found in the aquatic environment. The presence of PBDEs puts the health and survival of aquatic species at risk due to the various toxic effects associated with exposure to these compounds. The effects of a binary dietary mixture of PBDEs on innate immunity and disease susceptibility of juvenile Chinook salmon (Oncorhynchus tshawytscha) were examined in the present study. Salmon were fed roughly 1:1 mixtures of two environmentally predominant PBDE congeners, BDE-47 and BDE-99. The six resulting whole body total PBDE concentrations ranged from less than the limit of quantification to 184 ng/g, wet weight (ww). The innate immune system was assessed by using two in vitro macrophage function assays. Specifically, assays that examined the ability of head kidney macrophages to: (1) engulf sheep red blood cells (SRBCs); and (2) produce a respiratory burst, as determined by the production of a reactive oxygen species, specifically superoxide anion. Macrophages from salmon fed the BDE-47/99 mixture diets engulfed more SRBCs and produced greater superoxide anion than salmon fed the control diet. An increase in macrophage function was observed in fish with whole body total PBDE concentrations ranging from 2.81 ng/g, ww to 184 ng/g, ww. The mechanism for this increase in macrophage function due to PBDE exposure is currently unknown, but may be due to the ability of PBDEs to act as an endocrine receptor agonist and/or antagonist. Salmon exposed to the BDE-47/99 mixture diets were also challenged with the pathogenic bacteria, Vibrio (Listonella) anguillarum to determine disease susceptibility. Kaplan-Meier survival curves of fish exposed to the BDE-47/99 mixture and control diets were significantly different. The Cox proportional hazard risk ratios of disease-induced mortality in juvenile Chinook salmon with whole body concentrations of total PBDEs of 10.9, 36.8, and 184 ng/g, ww were significantly greater than the fish fed the control diet by 1.56, 1.83 and 1.50 times, respectively. Not all concentrations of the binary mixture diets had significant hazard ratios relative to the control diet, due to a non-monotonic concentration response curve. The mixture of PBDE congeners resulted in interactive effects that were generally non-additive and dependent upon the congener concentrations and metric examined. Consequently, predicting the interactive effects in juvenile Chinook salmon exposed to mixtures of PBDE congeners on innate immunity and disease susceptibility cannot be readily determined from the adverse effects of individual PBDE congeners.